Tissue factor (TF), the initiator of the extrinsic coagulation pathway, is upregulated in cancer cells and the complex of TF with its ligand coagulation factor VIIa (FVIIa) contributes to cancer- associated thrombosis and activation of the host hemostatic system in metastasis. In addition, cancer cell signaling of the TF-FVIIa complex, in cooperation with the TF cytoplasmic domain, promotes tumor progression in spontaneous murine and human xenograft models by activating proangiogenic cell signaling of the G protein-coupled protease activated receptor (PAR) 2. This pathway can be targeted to attenuate tumor growth in preclinical tumor models. In this renewal application, we address unresolved major questions on the roles of the TF pathway in tumor biology, utilizing newly developed genetic and pharmacological approaches. Aim 1 utilizes an integrin binding-impaired mutant of FVIIa to dissect integrin-dependent and -independent signaling of the TF-FVIIa complex. In addition, characterization of a novel mouse model carrying cleavage-insensitive PAR2 will provide the first definitive distinction of proteolytic and cleavage- independent bystander roles of PAR2 in tumor progression and metastasis. Aim 2 addresses the origin of upstream coagulation proteases that promote tumor growth by activating cancer cell-expressed protease receptors and delineates the respective contributions of FVIIa and FXa to cancer cell PAR2 activation. In Aim 3, the specific functions of TF splice variants in angiogenesis are further elucidated with novel genetic and pharmacological tools. The proposed studies are expected to yield valuable new insights into potential therapeutic approaches to block tumor promoting signaling of the coagulation pathway.